Abstract
Acrylonitrile (VCN) is a widely used industrial chemical. The present work examines the mechanism of its renal toxicity. In renal centrifugal fractions from Sprague-Dawley rats, the metabolism of VCN to cyanide (CN-) was highest in the microsomal fraction and required a NADPH-generating system in the presence of magnesium ions for maximum activity. This biotransformation of VCN to CN- was characterised with respect to time (15 min), microsomal protein concentration (3 mg ml(-1)), pH (7.5) and temperature (37 degrees C). The Trm,, of the reaction was 118.2 pmol CN- mg(-1) protein min(-1) and K-m was 160.2 mu mol VCN. Activation of VCN to CN- was markedly increased in microsomes obtained from phenobarbital (PB), ethanol, 4-methylpyrazole and 3-methylcholanthrene-treated rats by 161.5, 89.6, 71.0 and 50.2%, respectively. Addition of SKF 525-A (5 x 10(-4) M) or benzimidazole (2 mM) to the incubation mixtures significantly inhibited VCN metabolism by 66.6 and 78.8%, respectively. VCN metabolism to CN- was enhanced significantly by the addition of 10 mM of glutathione (GSH), L-cysteine, D-penicillamine, cysteamine or 2-mercaptoethanol to 389.5, 886.5, 611.1, 145.5 and 384.0% of control, respectively. These findings indicate that VCN is metabolised in the kidney via cytochrome P-450-dependent mixed function oxidase system. (C) 1999 Academic Press.